Clinical outcomes for Clostridioides difficile associated diarrhea in inflammatory bowel disease patients versus non-IBD population: A retrospective cohort study

Patients with inflammatory bowel disease (IBD) have a higher incidence of Clostridioides difficile infection (CDI). Previous studies have demonstrated negative clinical outcomes in IBD patients with CDI compared to patients without CDI. The clinical presentation of CDI is indistinguishable from IBD exacerbation, thus posing a frequent clinical dilemma on the role of Clostridioides infection in the testing, diagnosis, and treatment of these patients. To compare clinical outcomes of CDI in patients with IBD to those without IBD. Retrospective cohort of adult patients admitted to Rabin Medical Center Israel between the years 2014 and 2020 with a concurrent diagnosis of IBD and CDI. Matching 1:2 was performed between the IBD patients and the non-IBD population with respect to age and sex. Sixty-seven patients with IBD and 134 patients without IBD were included in the study. The groups’ median age was 40.6 (interquartile range [IQR] of 29.8–68.9), with 45.8% male and 54.2% female. The non-IBD group had a higher Charlson score with 2 (IQR 0; 5) versus 0 (IQR 0; 4) in the IBD group (P value <.01). Patients with IBD had more exposure to systemic antibiotics, 71.1% versus 26.3% (P value <.01). In a multivariable analysis we found no difference in 90-day mortality and rate of relapse between the 2 study groups with an odds ratio of 1.709 (95% confidence interval 0.321–9.905) and odds ratio of 0.209 (95% confidence interval 0.055–1.513) respectively. In our cohort patients with IBD who present with diarrhea and concomitant CDI have similar rates of relapse and mortality compared with patients without IBD.


Introduction
Clostridioides difficile (CD, formerly known as Clostridium difficile) is a gram-positive, fastidious, and spore-forming bacteria responsible for toxin-mediated infectious colitis associated with antibiotic use and healthcare interaction. [1] C. difficile infection (CDI) can manifest in a wide spectrum of severity from mild diarrhea to fatal pseudomembranous colitis and toxic megacolon. CDI is a nosocomial infection that can spread in an endemic and sporadic fashion. In 2019, CDI was diagnosed in 223,900 patients in the USA and accounted for 12,800 deaths. [2] Inflammatory bowel disease (IBD) is a spectrum of chronic, systemic immune-mediated diseases affecting primarily but not only the gastrointestinal tract. [3] The prevalence of IBD is on the rise in recent years. In a systematic review of the literature, Molodecky et al estimated an annual worldwide incidence of 5 to 24.3 per 100,000 person-years. [4] The occurrence of CDI is higher in patients with IBD. [5] In a retrospective study, by Rodemann et al, analyzing patients diagnosed with CDI showed an odds ratio (OR) of 2.9 (confidence interval [CI] 95% 2.1-4.1) for IBD versus non-IBD patients. In his study, the stool CD toxin was diagnosed in the first 48 hours of admission, implying the disease was mainly community-acquired. [6] The association between IBD and CDI is not completely understood and most likely comprise of an interplay between interrupted gastrointestinal mucosal barrier, frequent antibiotic exposure, recurrent hospitalizations, altered nutritional status, genetic predisposition, microbiome, and immune factors. [7] In a study evaluating 6932 patients with IBD in Greece, the prevalence of CDI was statistically significantly higher than in non-IBD hospitalized patients with 30/401 versus 309/6531. [8] Known risk factors for CDI are usually more common in IBD patients notably immunosuppression and systemic antibiotic exposure.
The sometimes indistinguishable clinical presentation of the 2 clinical syndromes, [9] complicates diagnosis, may cause delays in treatment, and presents dilemmas in treatment approaches. The long and short-term clinical outcomes of patients with CDI and IBD are worse than those of IBD exacerbation alone. [10][11][12] Interestingly, Gupta et al in a study evaluating 92 patients with IBD found that toxin enzyme-linked immunosorbent assay (ELISA) positive patients had a higher rate of response to anti-Clostridioides antibiotics compared to ELISA test negative and nucleic acid amplification test (NAAT) positive patients and had lower chances of requiring IBD therapy escalation. [13] In the post hoc analysis of MODIFY I/II, patients with a positive ELISA test had a more severe disease on one hand and a higher chance of treatment response on the other hand. [14] Similar results were demonstrated by Avni et al in the non-IBD population with lower 30-day all-cause mortality in the NAAT-positive patients. [15] The aim of this study is to compare the clinical outcomes of CDI in patients with and without IBD.

Methods
The study was conducted in Beilinson Hospital at Rabin Medical Center and included adult patients (age of ≥18 years old), admitted between the years 2014 and 2020 in medical or surgical wards with a concurrent diagnosis of IBD. CDI diagnosis was provided using a stool sample and evaluated by the C. DIFF QUIK CHEK COMPLETE assay (TechLab, Blacksburg, VA). This assay detects toxin A, toxin B, and glutamate dehydrogenase antigens. Discrepancy between the toxin and the glutamate dehydrogenase exam was solved using Xpert CD polymerase chain reaction assay (BD Gene-OhmTM Cdiff Assay; Franklin Lakes, NJ). The study was approved by Rabin Medical Center institutional review board (RMC-20-0928). Patients were considered to have Clostridioides disease and thus included in the study, were only those with a positive toxin test (defined as a positive ELISA test or positive antigen test together with a positive NAAT for the toxin). Patients with only positive antigen tests and negative toxin results were not included in the study and were not considered to have Clostridium disease based on current guidelines and recommendations. [16,17] Clinical data were collected retrospectively using electronic medical charts. Information regarding patients' general characteristics; background disease; IBD status; laboratory results, clinical presentation, and outcomes were collected electronically. Comorbidities were defined using the modified Charlson comorbidity index. [18] Patients were divided into an IBD group and a non-IBD group depending on IBD diagnosis prior to admission. Follow-up period was 90 days. The primary outcomes were time to resolution of the symptom; 90-day mortality; recurrence of infection; the need for colectomy and intensive care unit admission. Severe CDI was defined as a white blood cell count >15,000 cells/mL or serum creatinine value >1.5 mg/ dL. Fulminant CDI was defined as hypotension, shock, or surgery to megacolon. [19] Clinical cure was defined as the first day without diarrhea during the study follow-up. Patients and the public were not involved in any way in the design, conduct, reporting, or dissemination plans of the research. This is due to the retrospective nature of the study. The study was approved by Rabin Medical Center local ethics committee.

Statistical analysis
Statistical analysis was performed using IBM SPSS Statistics 27 (IBM, Armonk, NY). Continuous non-normally distributed variables were presented as median and interquartile range. All patients were matched 1:2 using sex and age as matching variables. Categorical variables and main comparisons of groups and outcomes were compared using chi square test. For adjusted comparison, binary logistic regression was used. All variables found clinically or statically significant were accounted for in the regression. A P value <.05 was considered significant.

Results
Our cohort included 201 patients with CDI, 67 patients with IBD, and 134 patients without IBD. The total study population had a median age of 40.6 and IQR of 29.8 to 68.9, 92/201 were male (45.8%) and 109/201 were female (54.2%), as presented in Table 1. The patients were different in their comorbidities, using the Charlson score, the median of the non-IBD group was 2 [IQR 0;5] versus 0 [0;4] in the IBD group (P value <.01). Moreover, the IBD group had more use of steroids in the 3 months prior to admission, 34/67 (59.6%) versus 29/134 (21.6%).
Clinical presentation and laboratory results were similar between the 2 groups regarding leukocytosis, kidney function, and recent hospitalization. IBD patients were more likely to present with a fever above 38 degrees 50.7% versus 14.9% in the non-IBD group (P value <.01). As expected, patients with IBD had more exposure to systemic antibiotics in the 3 months prior to CDI diagnosis, 71.1% versus 26.3% (P value <.01). On univariate analysis, patients with IBD were at similar risk to develop severe or complicated CDI 43.3% versus 37.3% (P value .414) and 4.5% versus 2.2% (P value .402) respectively, as presented in Table 3.
Regarding treatment, 89 of the 201 patients in the cohort were treated with enteral metronidazole -17.9% in the IBD group versus 57.5% in the non-IBD group. The use of vancomycin was similar between the 2 groups, while fidaxomicin was more commonly utilized in the IBD group with 9 versus 6 patients (P value <.05). The median length of hospital stay was 6 days [IQR 2; 15] and the number of days to symptoms resolution was higher in the IBD group with a median of 5 days [IQR 3; 15] versus 3 days [IQR 2; 7], although it failed to reach statistical significance.
Molecular diagnosis was different between the 2 groups with 14/67 (20.9%) being ELISA positive in the IBD group versus 64/134 (47.8%) in the non-IBD group (P value <.01). Although the mortality rate was higher in patients with a positive ELISA for toxin test compared to only positive NAAT result, it did not reach statistical significance either in the non-IBD or in the IBD group. No difference was demonstrated between the groups in 90-day mortality, the first event of relapse, hospital mortality, intensive care unit admission, and colectomy rates as presented in Table 3 and Figure 1. In a multivariable analysis, the OR for 90-day mortality was 1.709 (95% CI 0.321-9.905) and the OR for the first event of relapse was 2.89 (95% CI 0.055-1.513), as presented in Table 4.

Discussion
Our study compared the clinical characteristics and outcomes of 67 hospitalized CDI patients with IBD to those without IBD treated in the same center. The study population in the 2 groups was different in their basic characteristics. Patients with IBD had fewer comorbidities but clinically presented with more cases of fever; had more use of antibiotics prior to admission and had higher chances of being treated with steroids before admission.
The most common diagnostic modality in IBD patients was ELISA negative and NAAT for toxin positive. Although recent evidence shows a higher mortality rate with ELISA-positive patients compared with polymerase chain reaction, [15] our cohort did not demonstrate any difference between the groups. Although many studies describe the association of ELISApositive patients with more severe diseases, this finding might be related to disease burden and other unmeasured disease-related features that can be altered in a colon with IBD pathology. Nonetheless, NAAT-positive patients are considered to have CDI based on current guidelines. [16,17] Previous studies demonstrated that patients with IBD have a negative clinical outcome upon acquiring Clostridioides infection. [20][21][22] Furthermore, the best medical approach for a patient with IBD and CDI is an issue of frequent clinical dilemma. The decision to treat with immunosuppression alongside antibiotics is a matter of ongoing debate. In a survey of 169 gastroenterologists from the USA and Canada, a significant disagreement was described in the common practice for these populations of patients. [23] The clinical questions that arise from the current evidence are whether CDI serves as a prognostic factor accounting for the severity of IBD or whether the patients' outcomes are derived from the infection itself. The acquisition of Clostridioides infection in the IBD population is considered a risk factor for negative clinical outcomes. [21] This study aimed to evaluate the patient's outcomes from the CDI perspective, comparing the IBD patients to patients without IBD. Interestingly, when controlling for age and sex, we found similar rates of mortality and the risk of relapse between the IBD and non-IBD patients. While the study groups were different in their nature and risk factors, with respect to CDI, they had similar outcomes. This observation further establishes that CDI in the IBD population represents similar risk for adverse outcomes as the non-IBD population and needs to be treated and addressed accordingly.
Our study has several limitations. The cohort presented in the study was composed of a small and heterogenic population of patients that had different medical treatments for the Clostridioides infection. Patients with IBD were treated more frequently with vancomycin and fidaxomicin compared with non-IBD patients. In spite of that, all patients were treated according to published guidelines [19] and the treatment regimen escalated with regard to disease severity. Furthermore, fidaxomicin is a novel anti-CDI antibiotic that was assessed for IBD patients in a clinical trial only for pharmacokinetics. [24] The prospective treatment of fidaxomicin in IBD patients might have a significant potential benefit due to its microbiome-friendly properties and needs to be further assessed in the IBD population. Lastly, in this study, we examined the antibiotic treatment for CDI in IBD patients but did not explore the treatment regimens for IBD before and during hospitalization and so the effect of IBD treatment on the course of CDI and vice versa was not addressed.
In conclusion, patients with IBD that present with diarrhea and concomitant CDI have similar rates of mortality and relapse